Disruption of Cancer Metabolic SREBP1/miR-142-5p Suppresses Epithelial–Mesenchymal Transition and Stemness in Esophageal Carcinoma

Abstract

Elevated activity of sterol regulatory element-binding protein 1 (SREBP1) has been implicated in the tumorigenesis of different cancer types. However, the functional roles of SREBP1 in esophageal cancer are not well appreciated. Here, we aimed to investigate the therapeutic potential of SREBP1 and associated signaling in esophageal cancer. Our initial bioinformatics analyses showed that SREBP1 expression was overexpressed in esophageal tumors and correlated with a significantly lower overall survival rate in patients. Additionally, tumor suppressor miR-142-5p was predicted to target SREBP1/ZEB1 and a lower miR-142-5p was correlated with poor prognosis. We then performed in vitro experiments and showed that overexpressing SREBP1 in OE33 cell line led to increased abilities of colony formation, migration, and invasion; the opposite was observed in SREBP1-silenced OE21cells and SREBP1-silencing was accompanied by the reduced mesenchymal markers, including vimentin (Vim) and ZEB1, while E-cadherin and tumor suppressor miR-142-5p were increased. Subsequently, we first demonstrated that both SREBP1 and ZEB1 were potential targets of miR-142-5p, followed by the examination of the regulatory circuit of miR-142-5p and SREBP1/ZEB1. We observed that increased miR-142-5p level led to the reduced tumorigenic properties, such as migration and tumor sphere formation, and both observations were accompanied by the reduction of ZEB1 and SREBP1, and increase of E-cadherin. We then explored the potential therapeutic agent targeting SREBP1-associated signaling by testing fatostatin (4-hydroxytamoxifen, an active metabolite of tamoxifen). We found that fatostatin suppressed the cell viability of OE21 and OE33 cells and tumor spheres. Interestingly, fatostatin treatment reduced CD133+ population in both OE21 and OE33 cells in concert of increased miR-142-5p level. Finally, we evaluated the efficacy of fatostatin using a xenograft mouse model. Mice treated with fatostatin showed a significantly lower tumor burden and better survival rate as compared to their control counterparts. The treatment of fatostatin resulted in the reduced staining of SREBP1, ZEB1, and Vim, while E-cadherin and miR-142-5p were increased. In summary, we showed that increased SREBP1 and reduced miR-142-5p were associated with increased tumorigenic properties of esophageal cancer cells and poor prognosis. Cells 2020, 9, 7 2 of 15Preclinical tests showed that suppression of SREBP1 using fatostatin led to the reduced malignant phenotype of esophageal cancer via the reduction of EMT markers and increased tumor suppressor, miR-142-5p. Further investigation is warranted for the clinical use of fatostatin for the treatment of esophageal malignancy.

Targeting SREBP-1-Mediated Lipogenesis as Potential Strategies for Cancer

“…Overexpressing SREBP1 in OE33 cells leads to increased biological phenotypes, including colony formation, migration, and invasion, which is mediated by reduced mesenchymal markers (vimentin, zinc finger E-box binding homeobox 1 (ZEB1), N-cadherin) and increased epithelial markers (E-cadherin). Mechanistically, SREBP-1 can regulate T-cell factor 1/lymphoid enhancer factor 1 and their target proteins, such as CD 44 and cyclin D1, and increase the levels of SCD-1, phosphorylated GSK-3β, and nuclear β-catenin for the proliferation and metastasis of esophageal carcinoma ( 113 , 114 ). SREBP-1 and ZEB1 are potential targets of miRNA-142-5p, a tumor suppressor, and they are associated with tumor progression and poor prognosis ( 114 ).…”

“…Mechanistically, SREBP-1 can regulate T-cell factor 1/lymphoid enhancer factor 1 and their target proteins, such as CD 44 and cyclin D1, and increase the levels of SCD-1, phosphorylated GSK-3β, and nuclear β-catenin for the proliferation and metastasis of esophageal carcinoma ( 113 , 114 ). SREBP-1 and ZEB1 are potential targets of miRNA-142-5p, a tumor suppressor, and they are associated with tumor progression and poor prognosis ( 114 ). Moreover, the levels of PCK1 pS90, Insig1 pS207/Insig2 pS151, and SREBP-1 are associated with the tumor, metastasis stage, and progression of esophageal squamous cell carcinoma, suggesting PCK1 activity-regulated SREBP-1 as a potential target for the diagnosis and treatment of esophageal cancer ( 115 ).…”

Inhibitors of lipogenic enzymes as a potential therapy against cancer

“…Pharmacological inhibition of this protein could block the expression of lipogenic enzymes in cancer cells. Indeed, some small molecules such as fatostatin were found to block fatty acid synthesis by inhibiting the activation of SREBP‐1 153 and they reduced the malignant phenotype of esophageal cancer 154 …”

Construction and analysis of a ceRNA network and patterns of immune infiltration in bladder cancer

“…Two survival analyses were performed in the present study based on the selected components of a ceRNA network (including ELN, SREBF1, DSC2, TTLL7, DIP2C, SATB1, hsa-miR-20a-5p, and hsa-miR-29c-3p) and selected immune cells (including M0 macrophages, M2 macrophages, resting mast cells, and neutrophils). Overexpression of SREBF1 was associated with a poor prognosis and promoted metastasis of esophageal carcinoma cells, and inhibition of SREBF1 augmented the efficacy of immune checkpoint blockades (49,50). Downregulated expression of DIP2C was detected in breast cancer, especially in basal-like and HER-2 subtypes (51).…”